tbuckley/cabot-search huggingface dataset:
OS08.6.A QUALITY OF LIFE IN PATIENTS AND CAREGIVERS FOLLOWING RADIOTHERAPY FOR BRAIN METASTASES: LOWER HEALTH STATUS AND MORE SYMPTOMS OF ANXIETY
Authors: E van Grinsven, F Cialdella, T G G Vrolijk, M E P Philippens, J J C Verhoeff, M J E van Zandvoort
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The incidence of brain metastases (BMs) has been rising due to improvements in cancer treatment. Although survival rates are typically 3-4 months, more and more long surviving patients and their families are confronted with physical, practical, emotional, and cognitive consequences of disease and more effective treatments. Therefore, we investigated quality of life (QoL) in both patients and caregivers in the six months following radiotherapy (RT). METHODS To understand the impact of BMs on QoL for both patients and caregivers, we implemented the prospective Cohort for patient-reported Outcomes, Imaging and trial inclusion in Metastatic BRAin disease (COIMBRA) to examine all patients with BMs who received RT. 94 adult patients with BMs and their informal caregivers completed the same QoL-questionnaires for themselves (including EQ-5D-3L, EQ-VAS and HADS) before RT, one month, three months and six months after RT. Individual changes in QoL were evaluated using minimal clinically important differences as reported in previous literature. Trajectories of changes in QoL were assessed using mixed linear models with a growth curve approach. RESULTS On the group-level, growth models indicated stable QoL for both patients and caregivers over the six months following RT. However, individual trends showed variability in baseline levels and rate of change. That is, patients with higher baseline QoL, tend to experience larger decreases in QoL over time. A comparison of the trajectories of QoL indicated no differences between patients and caregivers. A closer inspection of the data, showed patients reported a lower health status (EQ-5D and EQ-VAS), while caregivers reported more symptoms of anxiety (HADS-anxiety) at all investigated time points (all p &amp;lt; .05). Over all time points considered, 37% of caregivers experienced clinically relevant symptoms of anxiety. Highest individual differentiated rates of change were seen in the first month following radiotherapy, with 34% of patients improving on the EQ-5D-3L whereas 42% of patients declined on the EQ-VAS. CONCLUSION Overall, in the six months following brain radiotherapy QoL remained stable in both patients and caregivers. Individual analyses highlights differentiated trajectories, with the majority of patients and caregivers showing the largest changes within the first month. Since a relatively large group of caregivers experienced symptoms of anxiety, this suggests a potential benefit for of offering psychological support to caregivers throughout the treatment process could potentially be beneficial. GRANT INFORMATION E.G was supported by research funding from the Dutch Cancer Society “Koningin Wilhelmina Fonds (KWF)” (#11110).
P17.08.A CLINICAL AND MOLECULAR CHARACTERIZATION OF EXTRACRANIAL METASTASES IN GLIOBLASTOMAS
Authors: J Jacobsen, C O'Rourke, A Locallo, J Carlsen, J Ewald, D Scheie, K Grunnet, A Schmidt, L Melchior, J Weischenfeldt, V Larsen, J Andersen, H Poulsen, H Broholm, S Michaelsen, B Kristensen
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults, but in contrast to many other malignancies they rarely metastasize. Metastasizing GBMs cause both diagnostic and therapeutic challenges and are generally poorly investigated. Therefore, our aim was to characterize these tumors clinically and molecularly. MATERIAL AND METHODS We collected and examined the largest cohort to date of tissue from 16 glioma patients (14 GBMs and 2 lower-grade gliomas) with extracranial metastases, including metastases to scalp (7) lymph nodes (5), bone (2), liver (1), and upper neck (1). After histopathological re-evaluation of the tumors, we assessed the associated magnetic resonance imaging (MRI) scans. Paired samples from the primary tumors, recurrences and metastases were investigated by next-generation sequencing (NGS) analysis with the TSO500 panel, genome-wide 850 K methylation profiling and immunohistochemistry followed by artificial intelligence-based quantification of markers of stemness and immune cells in the tumor microenvironment (TME). RESULTS Clinically, the patients were comparable to other GBM patients (gender, age, treatment, and survival). 12/16 patients developed one or more intracranial recurrence(s). MRI scans revealed proximity of the brain tumors to dura, large vessels, and ventricles in a high proportion of the patients. Moreover, we found that (6/7) scalp lesions were in fact extracranial extensions of the brain tumors. NGS data showed that the metastases were clonally derived from the primary tumors and not from the brain recurrences. Methylation- and copy number analysis overall confirmed the initial diagnoses and revealed a patient-specific signature across paired samples in a majority of the patients. Additionally, we observed methylation subclass switch during tumor progression and identified differentially methylated regions enriched in the olfactory transduction pathway when comparing metastases to primary tumors. Levels of tumor stemness were generally preserved according to methylation-based stemness index and OLIG2 and SOX2 protein expression. Similarly, the composition of immune cells in the TME did not change significantly, as shown by cell-type deconvolution and immune cell quantification. CONCLUSION Extracranial metastases occurred as early events and overall preserved the tumor- and TME characteristics of the primary brain tumors. Factor such as brain tumor location, neurosurgery and epigenetic regulation of genes associated with olfactory transduction could be involved in glioblastoma metastasis.
KS01.5.A LATE BREAKING ABSTRACT: LONG-TERM FOLLOW-UP OF PATIENTS WITH NEWLY DIAGNOSED IDH-MUTANT ASTROCYTOMA AFTER IDH1-VAC TREATMENT
Authors: L Bunse, K Lindner, A Wick, I Poschke, A Freitag, D Edelmann, L Lanz, M Breckwoldt, F Sahm, A Schmitt, O Schnell, J Hense, M Misch, D Krex, M Denk, J Steinbach, A von Deimling, M Schmitt, G Tabatabai, M Bendszus, W Wick, M Platten
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The Neurooncology Working Group of the German Cancer Society trial 16 (NOA16), a multicenter, single-arm, open-label, first-in-human phase I trial, met its primary endpoints in demonstrating safety and immunogenicity of a long peptide vaccine targeting IDH1(R132H) (IDH1-vac) added to standard of care in 32 patients with newly diagnosed World Health Organization (WHO) Grade 3 (n=21) and 4 (n=11) IDH1(R132H)+ astrocytomas (ClinicalTrials.gov identifier NCT02454634). MATERIAL AND METHODS Here, we report on the clinical and immunological long-term follow-up of NOA16. Data cut-off was May 2023. RESULTS Six-year progression-free and survival rates of patients in the safety data set were 0.47 (CI: 0.29 - 0.63) and 0.66 (CI: 0.46 - 0.79), respectively. Six-year progression-free and survival rates in the Grade 3 population were 0.52 (CI: 0.30 - 0.71) and 0.67 (CI: 0.43 - 0.83), respectively. Six-year progression-free and survival rates in the Grade 4 population were 0.55 (CI: 0.23 - 0.78) and 0.62 (CI: 0.28 - 0.84), respectively. Six-year progression-free and survival rates in patients with complete resection (n=17) were 0.82 (CI: 0.55 - 0.94) and 0.88 (CI: 0.61 - 0.97), respectively. Calculated via the Simon-Makuch method, patients in the immunogenicity dataset (n=30) with immune responses (IR) had six-year progression-free and survival rates of 0.46 (0.26 - 0.64) and 0.75 (CI: 0.55 - 0.87), respectively. Two patients without IR showed progressive disease (PD) within two years of first diagnosis and died within 3 years of first diagnosis. In one-year landmark analyses, best mutation-specific B cell response at the time point of last vaccination or later was associated with a favorable clinical course, suggesting a relevant but differential response to repetitive therapeutic vaccination regimes. CONCLUSION This data supports a randomized clinical trial of IDH-vac in patients with newly diagnosed IDH-mutant gliomas. A booster treatment regime should be considered as continuous source of IDH1R132H-reactive T cells.
JS08.4.A LINEAR GRADING COEFFICIENT REVEALS EMBRYONIC DEVELOPMENT GENE SIGNATURE AS TREATMENT-INDEPENDENT PROGNOSTIC FACTOR IN IDH-MUTANT ASTROCYTOMA
Authors: S A Ghisai, Y Hoogstrate, C M S Tesileanu, L van Hijfte, I de Heer, W R Vallentgoed, M J van den Bent, P J French
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Diffuse gliomas are classified into grade II/III and grade IV IDH-mutant (IDHmt) astrocytoma based on histology and homozygous deletion of the CDKN2AB locus, according to the 2021 WHO classification. There is considerable variation in prognosis within these classification groups and we therefore sought to identify features that might aid further tumor grading. MATERIAL AND METHODS RNA sequencing was performed on IDHmt astrocytomas included in the CATNON trial and overlaid with previously generated genome-wide methylation data. This dataset was extended by multi-omics data from the TCGA and GLASS-NL studies, where the latter was used for validation. For all datasets, only IDHmt astrocytomas were selected. We defined a linear grading coefficient (LGC) based on calibrated DNA methylation-based probability scores and performed differential gene expression (DGE) regression analysis on the LGC. Statistical analyses were intersected across the CATNON and TCGA cohorts ("discovery set") and validated on the primary-recurrent GLASS-NL dataset. Single-nucleus RNA-sequencing (snRNAseq) data of high-grade IDHmt astrocytomas was used to explore the source of expression signals. RESULTS DGE regression analysis revealed that higher-grade IDHmt tumors (high LGC) exhibited mRNA upregulation of key embryonic developmental transcription factors (HOXA/C/D, NKX, PAX, and TBX). Although the vast majority of CpG sites in LGC high tumors were hypomethylated, homeobox genes were strongly hypermethylated in our discovery set. All HOX gene clusters showed gene-ordered (differential) expression where e.g. HOXD10&amp;gt;D9&amp;gt;D8&amp;gt;D4&amp;gt;D1 and HOXA3&amp;gt;A7&amp;gt;A9&amp;gt;A13 suggesting derepression of enhancer sequences up/downstream of the gene cluster. Our expression-based gene signature was positively correlated with, but not limited to, the G-CIMP-low subtype and homozygous CDKN2AB deletion. More than half of the genes from the HOX gene family were part of our signature. Our embryonic development signature was prognostic (log-rank test) on both the discovery (CATNON: p &amp;lt; 0.0005, TCGA: p &amp;lt; 0.0005) and validation set (GLASS-NL: p &amp;lt; 0.005). As our signature was developed on molecular data from the first resection its prognostic value is treatment-independent. SnRNAseq on high-grade IDHmt astrocytomas indicated expression of embryonic development genes from tumor cells, which was not restricted to cells from the stemness program. CONCLUSION Our study highlights upregulation of embryonic development genes as potential molecular mechanism associated with the malignant progression of IDH-mutant astrocytomas.
P20.09.A FRACTIONATED STEREOTACTIC RADIOTHERAPY (FSRT) AS A TREATMENT FOR TRIGEMINAL SCHWANNOMAS
Authors: L F ARMIJOS, M Maciá, A Lucas, N García
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Trigeminal schwannomas (TS) represent 1-8% of all intracranial schwannomas and 0.1-0.5% of all intracranial tumors Treatment strategies are mainly based on limited published data and case reports. The most common treatment is surgical resection. However, it can rarely be completed. Fractionated stereotactic radiotherapy (FSRT) has the potential to be a valuable and safe alternative to control growing or symptomatic TS. The aim of this review is to analyze clinical RESULTS , toxicity and tumor control rates obtained with this technique when treating this pathology in our short series of cases. MATERIAL AND METHODS Medical records of 18 patients treated from January 2007 to December 2018 were reviewed. 15 of them presented symptoms at the moment of diagnosis (83.3%) and the remaining 3 were radiological findings. Surgery was previously performed in 2 cases. Regarding radiotherapy scheme, all patients received 1.8-2Gy daily fractions to a median of 50,0 Gy. The median follow-up time was 62.7 months. RESULTS The outcome after radiotherapy was favourable in 16 of 18 patients (88.8%), clinical improvement was achieved in 52.94% while stability of symptoms was reached in 35.29%. Tumor growth was controlled in 82.35% of cases, even with tumor decrease observed in 5.88%. Acute toxicity was detected in 23.53% and it consisted in increased pain, sensitive alterations and diplopia. All well tolerated with adjusted corticoids and pain medication scheme. Clinical worsening and radiographic progression was shown in 2 out 17 patients and surgery was needed as salvage treatment in both cases (11.76%). However, one of them presented these outcomes in a period in which pseudoprogression could not be excluded (less than 2 years after treatment). CONCLUSION FSRT such as primary or adjuvant treatment accomplishes good clinical results and tumoral control, being an alternative for those patients with comorbidities not suitable for a surgical treatment or who preferred a non-invasive treatment. Regarding toxicity, FSRT is mainly a well tolerated treatment among patients. Prospective multicenter studies should be run in order to accomplish statistically significant results. Also, it is the second case series that reports the flare effect.
P11.49.B STEREOTACTIC RADIOSURGERY FOR CRANIAL AND SPINAL HEMANGIOBLASTOMAS: A SINGLE-INSTITUTION SERIES
Authors: K H Yoo, D J Park, N J Marianayagam, X Gu, E L Pollom, S G Soltys, S D Chang, A Meola
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Stereotactic radiosurgery (SRS) has been an attractive treatment modality for both cranial and spinal hemangioblastomas, especially for multiple lesions commonly associated with von Hippel-Lindau (VHL) disease. This study aims to provide the largest long-term analysis of treatment efficacy and adverse effects of SRS for cranial and spinal hemangioblastomas at a single institution. MATERIAL AND METHODS We evaluated the clinical and radiological outcomes of patients with hemangioblastomas treated with CyberKnife SRS at our institute from 1998 to 2022. The follow-up data were available for 135 hemangioblastomas in 35 patients. Twenty-eight patients had 123 hemangioblastomas associated with VHL and 7 had 12 sporadic hemangioblastomas. The median age was 36 years and the median tumor volume accounted for 0.4 cc. The SRS was administered with the median single-fraction equivalent dose (SFED) of 18 Gy to the 77% median isodose line. RESULTS At a median follow-up of 57 months (range: 3-260), only 20 (16.2%) of the VHL-associated and 1 (8.3%) sporadic hemangioblastomas progressed. The 5-year local tumor control (LTC) rate was 91.3% for all hemangioblastomas, 91.7% among the sporadic lesions, and 92.9% in VHL patients. SRS improved tumor-associated symptoms of 98 (74.8%) of 131 symptomatic hemangioblastomas, including headache, neck pain, dizziness, visual disturbances, dysesthesia, ataxia, motor impairment, seizures, and dysphagia. Two patients developed radiation necrosis (5.7%) and 1 of them required surgical resection. CONCLUSION SRS is a safe and effective treatment option for patients with hemangioblastomas in critical locations such as the brainstem, cervicomedullary junction, and spinal cord, and in patients with multiple hemangioblastomas associated with VHL disease.
P11.59.B HIGH GRADE GLIOMAS IN PATIENTS WITH HISTORY OF EXTRACRANIAL CANCERS, A RETROSPECTIVE MULTICENTRIC STUDY
Authors: O Kalita, T Kazda, S Reguli, R Jancalek, P Fadrus, M Slachta, P Pospisil, L Krska, J Vrbkova, J Cvek, M Dolezel, M Smrcka, R Lipina, L Hrabalek
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Metastases are most frequent brain cancer, involving 50-60% of all intracranial neoplasm. Dominated origins are lung, breast, colorectal cancers. A progress in diagnostic and treatment strategies significantly improved the life expectancy of patients with extracranial cancers. Patients with neurological symptoms should be recommended to the brain MRI. Rarely silent primary brain cancers are revealed. Metastases are considered as a first option, but brain lesions with contrast enhancement could be misdiagnosed. We more and more often meet with high grade glioma (HGG) in patients experienced with other primary cancer. Aim of our study is evaluated an incidence of concurrent cancers, relations between former cancer staging and malignant primary brain tumor evaluation, and also appreciation of treatment efficiency. MATERIAL AND METHODS Data of all glioma patients treated at the three Czech neuro-oncology centers are collected regularly and prospectively during routine maintenance of a database. This work focuses on adult patients with concurrent history both of extracranial cancers and HGGs who underwent resection and oncotherapy between January 2008 and December 2020. Information on the patients’ clinical condition (Karnofsky score (KS)) was collected along with imaging and histological data on each patient’s tumor and details of their cytogenic alterations. Also regarding former extracranial cancers they have been followed up by oncologic center. We excluded the patients with prostate cancer. RESULTS The analysis included 48 patients aged between 44 and 79 years. The median age was 65.3 years. The group contained more women (35/48) than men (13/48). Thirty one patients had a history of breast carcinoma, nine of renal carcinomas and eight of colorectal carcinomas. Following the diagnosis of carcinoma, forty four patients received oncotherapy and four had no adjuvant therapy. Surgery of brain tumors has always revealed HGGs, IDH wild-type. Following the diagnosis HGG thirty patients underwent chemoradiotherapy, thirteen had palliative radiotherapy and five had no oncotherapy. The average time from the diagnosis of extracranial cancer to that of GBM was 4 years. The OS was 11.4 months (range 3-29 months). All the patients succumbed to GBM progression. CONCLUSION Limited number of these patients has been selected. Prognosis was depended on staging of extracranial cancer and performance status. If these patients would be able to pass standard oncologic treatment of primary HGG, they did not find survival distinctions to compare with no extracranial cancer history patients. For right treatment strategy it is mandatory to eliminate misdiagnose of brain metastases and primary malignant brain tumors. This research was funded and supported by Ministry of Health of the Czech Republic (grant NU21-03-00195, NU20-03-00148)
P07.03.A COMPLETE LONG-LASTING RESPONSE TO MULTIMODAL THIRD LINE TREATMENT WITH NEUROSURGICAL RESECTION, CARMUSTINE WAFER IMPLANTATION AND DABRAFENIB PLUS TRAMETINIB IN A BRAFV600E MUTATED HIGH-GRADE GLIOMA
Authors: C Fonte, B Castelli, M Tellini, M Guidi, L Giunti, M Di Nicola, A Buccoliero, C Caporalini, I Desideri, D Greto, L Genitori, I Sardi
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND BRAF mutations are drivers of oncogenesis in a variety of tumors and they can be successfully targeted with small molecule inhibitors. In primary central nervous system tumors, BRAFV600E mutations are most frequently found in pleomorphic xanthoastrocytoma, ganglioglioma, pilocytic astrocytoma and epithelioid glioblastoma. Dabrafenib is a potent and selective inhibitor of BRAF-mutant kinase that was approved, as monotherapy or in combination with trametinib (mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor), for unresectable or metastatic BRAF-mutated melanoma, advanced non-small cell lung cancer and anaplastic thyroid cancer harboring BRAFV600E mutation. MATERIAL AND METHODS In February 2016, a 21-year-old female was admitted to our Unit for seizures. A brain magnetic resonance imaging (MRI) revealed a frontal contrast enhanced lesion. Neurosurgical resection was performed. The histological analysis diagnosed anaplastic pleomorphic xanthoastrocytoma (PXA) WHO grade III. A volumetric modulated radiotherapy course was delivered for a total dose of 59,4 Gy in 33 fractions with concomitant and adjuvant temozolomide therapy (Stupp protocol). In October 2017, a brain MRI showed relapsing disease. Six courses of chemotherapy with procarbazine, lomustine and vincristine (PCV) were administered, and then neurosurgical partial removal and carmustine wafer implantation were performed. The histological analysis confirmed BRAF V600E mutated anaplastic PXA. RESULTS In April 2019 the 24-year-old female patient with BRAF mutated anaplastic PXA started her third-line therapy with dabrafenib. The well-known tumor residue was less evident on the subsequent MRIs performed every three/four months. Given the literature data of the most effectiveness and the best control of the side effects, in August 2020 the patient was put on combined treatment with dabrafenib plus trametinib. Since December 2021 the residual tumor has not been longer visible. Last MRI evaluation, performed on January 26th 2023, showed no recurrence of the disease, four years after BRAF inhibitor treatment beginning. CONCLUSION Dabrafenib plus trametinib is a promising new therapy for patients affected by BRAFV600E-mutant glioma, with high overall response and manageable toxicity. Due to very poor prognosis, there are a few described cases of high-grade glioma (HGG) patients in third-line therapy, showing complete response and for such a long time. The emergence of optimized sequencing strategies and targeted agents, including multimodal treatment and systemic therapy with dabrafenib plus trametinib, will continue to broaden personalized therapy in HGG and to improve patient outcomes.